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Biscyclopeptide E(c(RGDfK))2 and preparation method thereof

A bicyclic peptide, fmoc-l- technology, applied in the field of cyclic peptides, can solve problems such as poor stability

Inactive Publication Date: 2017-07-04
ANHUI UNIVERSITY OF TECHNOLOGY AND SCIENCE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the cyclic RGD pentapeptide has the above-mentioned excellent characteristics, its stability is poor

Method used

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  • Biscyclopeptide E(c(RGDfK))2 and preparation method thereof
  • Biscyclopeptide E(c(RGDfK))2 and preparation method thereof
  • Biscyclopeptide E(c(RGDfK))2 and preparation method thereof

Examples

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preparation example Construction

[0025] The invention provides a bicyclic peptide E[c(RGDfK)] 2 The preparation method, this preparation method comprises:

[0026] 1) Soak the resin and Fmoc-Asp-oall (Fmoc-L-aspartic acid alpha-allyl ester) in DCM (dichloromethane), then add DIEA (N,N-diisopropylethylamine) Perform a contact reaction followed by washing;

[0027] 2) Add DCM, methanol and DIEA to the reaction system for capping treatment, then add piperidine for deprotection, and then wash until the reaction system is detected as blue by ninhydrin;

[0028] 3) G (glycine), HoBt (1-hydroxybenzotriazole), TBTU (O-benzotriazole-N, N, N', N'-tetramethylurea tetrafluoroborate) Add to the reaction system for contact reaction, and then wash until the reaction system is detected as blue by ninhydrin;

[0029] 4) Add R (arginine), K (lysine), and f (phenylalanine) to the reaction system in turn for contact reaction, and then add Pd (PPh 3 ) 4 (Tetrakis(triphenylphosphine)palladium) to carry out propenyl removal re...

Embodiment 1

[0056] Preparation of Bicyclic Peptide E[c(RGDfK)] 2

[0057] a. Weigh 1g of 2-cl resin, soak it in 20mL of DCM at 20°C for 2min, then wash once with DMF and DCM; use 20mL of DCM as solvent, weigh 0.5g of Fmoc-Asp-oall, mix with 1mL of DIEA, 1g of 2-cl resin was reacted at 20°C for 2h, and then washed twice with DMF; capped with 20mL DCM+1mL methanol+1mL DIEA at 20°C for 30min, washed three times with DMF; desorbed with 15mL piperidine at 20°C Protected, reacted for 15 minutes, and then washed 4 times with DMF until ninhydrin was detected as blue;

[0058] b. Add 0.9gG and 0.5mg HoBt to the system, add 1g TBTU as catalyst, 20mL DMF as solvent, react at 20°C for 1h, then wash 3 times until ninhydrin is detected as blue; add 2g R, 1.6 g K, 1.2g f were reacted at 20°C for 45 minutes;

[0059] c, with 1.2g of Pd (PPh 3 ) 4 , react at 20°C for 2h to remove the propenyl group; deprotect with 15mL piperidine at 20°C for 15min, then wash with DMF, DCM, and methanol in sequence un...

Embodiment 2

[0062] Preparation of Bicyclic Peptide E[c(RGDfK)] 2

[0063] a. Weigh 1g of 2-cl resin, soak it in 30mL of DCM at 25°C for 5min, then wash once with DMF and DCM; use 30mL of DCM as solvent, weigh 0.6g of moc-Asp-oall, and 1.5mL of DIEA , 1g of 2-cl resin was reacted at 25°C for 3h, and then washed twice with DMF; capped with 30mL DCM+1.5ml methanol+1.5mL DIEA at 25°C for 50min, washed 3 times with DMF; washed with 20mL piperidine at 25 Deprotect at ℃, react for 30 minutes, then wash with DMF 4 times until ninhydrin is detected as blue;

[0064] b. Add 1gG and 0.6g HoBt to the system, add 1.5g TBTU as catalyst, 30mL DMF as solvent, react at 25°C for 1.5h, then wash 3 times until ninhydrin is detected as blue; add 2.5g R, 2g K, 1.5g f were reacted at 25°C for 1h;

[0065] c, with 1.5g of Pd (PPh 3 ) 4, react at 25°C for 3h to remove the propenyl group; use 20mL piperidine to deprotect at 25°C for 30min, then wash with DMF, DCM, and methanol in sequence until the eluted was...

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Abstract

The invention discloses a biscyclopeptide E(c(RGDfK))2 and a preparation method thereof. The method comprises the following steps: 1) immersing resin and Fmoc-Asp-oall (Fmoc-L-aspartic acid alpha-allyl ester )in DCM (dichloromethane), adding DIEA (N,N-diisopropylethylamine), carrying out a contact reaction, and washing the obtained reaction product; 2, adding DCM, methanol and DIEA to the above obtained system, carrying out end capping treatment, and adding piperidine to carry out deprotection; 3) adding G (glycine), HoBt (1-hydroxybenzotriazole) and TBTU (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate) to the reaction system, and carrying out a contact reaction; 4) sequentially adding R (arginine), K (lysine) and f (phenylalanine) into the reaction system, carrying out a contact reaction, adding Pd(PPh3)4, carrying out a propenyl group removal reaction, and adding piperidine to carry out deprotection; 5) adding DIEA, HoBt and HBTU into the system, carrying out a contact reaction, adding a hydrazine hydrate and DMF mixed solution, carrying out a secondary reaction, and washing the obtained reaction product to remove Dde; 6) dropwise adding Fmoc-Glu-OH, HoBt, DMF and TBTU to the reaction system, carrying out a contact reaction, and washing the obtained reaction product; and 7) adding piperidine to the reaction system to carry out deprotection, washing the obtained product with DMF, DCM and methanol, and carrying out post-treatment to obtain the biscyclopeptide E(c(RGDfK))2. The biscyclopeptide E(c(RGDfK))2 has excellent stability.

Description

technical field [0001] The present invention relates to cyclic peptides, in particular to bicyclic peptide E[c(RGDfK)] 2 and its preparation method. Background technique [0002] All organs in the human body are composed of cells. Orderly cell growth and differentiation meet the body's needs and maintain good health. However, if the cells continue to divide, no longer under the control of the body, and reproduce indefinitely, these extra large numbers of cells form a tumor. Cells of malignant tumors can invade and destroy adjacent tissues and organs. Also, cancer cells can break out of the tumor and enter the blood or lymphatic system, becoming life-threatening. [0003] At present, many anti-tumor drugs have been developed, and all of them have effective pharmacological activities, but their poor solubility, will be cleared quickly in the body, and have certain toxicity and side effects, which limit their clinical application. [0004] In drug research and development,...

Claims

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Application Information

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IPC IPC(8): C07K7/64C07K1/06C07K1/04
CPCC07K7/64
Inventor 葛飞乔茜茜陶玉贵朱龙宝李婉珍宋平江志超
Owner ANHUI UNIVERSITY OF TECHNOLOGY AND SCIENCE
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